Discovery, synthesis and in silico approach of pyrrolo [3,4-c]pyrroles as SARS-CoV-2 m^pro inhibitors

Abstract

A new coronavirus has been identified as the contributing agent of the severe acute respiratory syndrome (SARS). The main viral protease (M^pro), which controls the activities of the coronavirus replication complex, which is an essential target for the treatment of coronavirus disease. With the primary objective of targeting this receptor, we designed a new series of pyrrolo [3,2-c] pyrroles, synthesized and characterized using various analytical techniques including FT-IR, UV-Vis and NMR spectroscopic studies. The biological descriptors of the synthesized compounds were investigated using DFT calculation. The mode of binding and reactivity of the target compounds with SARS-CoV-2 main protease (M^pro) were studied using molecular docking and molecular dynamics (MD) simulation. Molecular docking of the compounds (4a and 5a) showed a promising binding affinity towards M^pro protein with the binding energy of −7.8 kcal/mol and −7.0 kcal/mol, respectively. The results of MD simulation and prime MM-GBSA calculation were consistent with molecular docking. The absorption, distribution, metabolism and excretion (ADME) properties of the compounds are in the acceptable range, as they are orally active and obey Lipinski’s rule of five without violation. In addition, in silico toxicity prediction using the Pro-Tox II revealed the non-toxic nature of the compounds. Hence the obtained results suggest that these compounds could be a possible anti-viral candidate and highlight this series of compounds for further drug design and development against SARS-CoV-2.

Communicated by Ramaswamy H. Sarma

Keywords:

• Pyrrolo [3,2-c]pyrroles
• [3 + 2]cycloaddition reaction
• SARS-CoV-2 M^pro
• molecular docking and dynamics simulation
• density functional theory
• anti-viral agent

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The author acknowledges the management board and Department of Chemistry, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India for financial support for this work. The author also acknowledges the Sophisticated Analytical Instrumental Facility (SAIF), Cochin University of Science and Technology (CUSAT), Kochi for providing NMR facility.